Crystalline forms of (r)-8-chloro-1-methyl- 2,3,4,5-tetrahydro-1h-3-benzazepine hydrochloride

ABSTRACT

The present invention is directed to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, compositions containing the same and uses thereof.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of the 5-HT_(2C)agonist, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride, compositions thereof and methods of using the same.

BACKGROUND OF THE INVENTION

Serotonin (5-HT) neurotransmission plays an important role in numerousphysiological processes both in health and in psychiatric disorders. Asan example, 5-HT has been implicated in the regulation of feedingbehavior. It is believed that 5-HT induces a feeling of fullness orsatiety so that eating stops earlier and fewer calories are consumed. Asthe 5-HT_(2C) receptor is expressed in high density in the brain(notably in the limbic structures, extrapyramidal pathways, thalamus andhypothalamus i.e. PVN and DMH, and predominantly in the choroid plexus)and is expressed in low density or is absent in peripheral tissues,development of a selective 5-HT_(2C) receptor agonist is desirable,having improved efficacy and safety over other anti-obesity agents andrelated drugs.

The compound, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine,whose structure is shown below in Formula I, belongs to a class of5-HT_(2C) agonists that are useful in the treatment of a number of5-HT_(2C)-related diseases and disorders, such as those mentioned above.Preparation and characterization of this compound are described in WO2003/086306, which is incorporated herein by reference in its entirety.Preparation and characterization of the hydrochloric acid salt of thiscompound is also described in International Application No.PCT/US04/19279 which is incorporated herein by reference in itsentirety. Because drug compounds having, for example, improvedstability, solubility, shelf life, and in vivo pharmacology, areconsistently sought, there is an ongoing need for new or purer salts,hydrates, solvates, and polymorphic crystalline forms of existing drugmolecules. The crystalline forms of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridedescribed herein help meet this and other needs.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a thermogravimetric analysis (TGA) thermogram forcrystalline Form I of the invention (TA Instruments TGA Q500 in opencell; 25-350° C.; 10° C./min).

FIG. 2 depicts a differential scanning calorimetry (DSC) thermogram forcrystalline Form I of the invention (TA Instruments DSC Q1000; 25-220°C.; 10° C./min).

FIG. 3 depicts a powder X-ray diffraction pattern (XRPD) for a samplecontaining crystalline Form I (PANalytical X'Pert Plus Powder X-RayDiffractometer; 5.0°-50.0° 2θ).

FIG. 4 depicts a dynamic vapor sorption (DVS) scan for crystalline FormI of the invention (VTI dynamic vapor desorption analyzer).

FIG. 5 depicts a thermogravimetric analysis (TGA) thermogram forcrystalline Form II of the invention (TA Instruments TGA Q500 in opencell open cell; 25-350° C.; 10° C./min).

FIG. 6 depicts a differential scanning calorimetry (DSC) thermogram forcrystalline Form II of the invention (TA Instruments DSC Q1000; 25-220°C.; 10° C./min).

FIG. 7 depicts a powder X-ray diffraction pattern (XRPD) for a samplecontaining crystalline Form II (PANalytical X'Pert Plus Powder X-RayDiffractometer; 5.0°-50.0° 2θ).

FIG. 8 depicts a dynamic vapor sorption (DVS) scan for crystalline FormII of the invention (VTI dynamic vapor desorption analyzer).

FIG. 9 depicts a thermogravimetric analysis (TGA) thermogram forcrystalline Form III of the invention (TA Instruments TGA Q500 in opencell open cell; 25-350° C.; 10° C./min).

FIG. 10 depicts a differential scanning calorimetry (DSC) thermogram forcrystalline Form III of the invention (TA Instruments DSC Q1000; 25-220°C.; 10° C./min).

FIG. 11 depicts a powder X-ray diffraction pattern (XRPD) for a samplecontaining crystalline Form III (PANalytical X'Pert Plus Powder X-RayDiffractometer; 5.0°-50.0° 2θ).

FIG. 12 depicts a dynamic vapor sorption (DVS) scan for crystalline FormIII of the invention.

SUMMARY OF THE INVENTION

In some embodiments, the present invention provides(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments, the present invention provides(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate having crystal Form III.

In some embodiments, the present invention provides(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideForm I.

In some embodiments, the present invention provides(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideForm II.

In some embodiments, the present invention provides compositionscomprising the crystalline forms of the invention.

In some embodiments, the present invention provides processes forpreparing the crystalline forms of the invention as well as crystallineforms prepared by the processes.

In some embodiments, the present invention provides methods formodulating a 5HT_(2C) receptor comprising contacting said receptor witha crystalline form herein.

In some embodiments, the present invention provides methods of treatingdisorders of the central nervous system; damage to the central nervoussystem; cardiovascular disorders;

gastrointestinal disorders; diabetes insipidus, or sleep apnea byadministering to a patient in need a therapeutically effective amount ofa hemihydrate or crystal form described herein.

In some embodiments, the present invention provides methods ofdecreasing food intake of a mammal comprising administering to saidmammal a therapeutically effective amount of a hemihydrate or crystalform described herein.

In some embodiments, the present invention provides methods of inducingsatiety in a mammal comprising administering to said mammal atherapeutically effective amount of a hemihydrate or crystal form asdescribed herein.

In some embodiments, the present invention provides methods ofcontrolling weight gain of a mammal comprising administering to saidmammal a therapeutically effective amount of a hemihydrate or crystalform as described herein.

In some embodiments, the present invention provides methods of treatingobesity comprising administering to a patient a therapeuticallyeffective amount of a hemihydrate or crystal form as described herein.

In some embodiments, the present invention provides use of a compound orcrystal form of the invention for use in therapy.

In some embodiments, the present invention provides use of a compound orcrystal form of the invention for use in the preparation of a medicamentfor use in therapy.

DETAILED DESCRIPTION Crystalline Forms

The present invention provides, inter alia, three crystalline forms of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride,individually designated as Form I, Form II, and Form III. Forms I and IIare anhydrous, hygroscopic forms, both of which readily convert to FormIII, a hemihydrate, upon exposure to moisture.

The various crystalline forms of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecan be identified by their unique solid state signatures with respectto, for example, differential scanning calorimetry (DSC), X-ray powderdiffraction (XRPD), and other solid state methods. Furthercharacterization with respect to water or solvent content of thecrystalline forms can be gauged by any of various routine methods suchas thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), DSCand other techniques. For DSC, it is known that the temperaturesobserved will depend upon the rate of temperature change as well assample preparation technique and the particular instrument employed.Thus, the values reported herein relating to DSC thermograms can vary byplus or minus about 4° C. For XRPD, the relative intensities of thepeaks can vary, depending upon the sample preparation technique, thesample mounting procedure and the particular instrument employed.Moreover, instrument variation and other factors can often affect the2-theta values. Therefore, the peak assignments of diffraction patternscan vary by plus or minus about 0.2°. The physical propertiesdistinguishing each of the three crystalline forms of the invention aresummarized in Table I below.

TABLE 1 Form I Form II Form III TGA FIG. 1; FIG. 5; FIG. 9; negligibleweight loss negligible weight loss 3.7% water loss below 150° C. below150° C. DSC FIG. 2; FIG. 6; FIG. 10; 201° C. (melt) 201° C. (melt) 95°C. (dehydration); 200° C. (melt) XRPD FIG. 3; FIG. 7; FIG. 11; 11.4°unique 13.7°, 14.9°, 15.4°, 15.8°, 16.7°, 8.9° unique DVS FIG. 4; FIG.8; FIG. 12; hygroscopic; hygroscopic; non-hygroscopic; adsorptiontransition at adsorption transition at adsorption of less than 0.5%about 60% RH; about 40% RH; at 90% RH; adsorbs about 3.8 wt %; adsorbsabout 3.8 wt %; deliquescent above 95% RH; deliquescent above 90%deliquescent above 90% no change in crystalline form RH; RH; aftercycle. crystalline form changes crystalline form changes to Form IIIafter cycle. to Form III after cycle habit granular rodsneedle/rods(CH₂Cl₂/hexanes) thin-plates (toluene/MeOH) block(cyclohexane/IPA)

The absence of weight loss below 150° C. in the TGA data suggests thatboth Forms I and II are anhydrous, non-solvated crystal forms. Thisresult is in contrast with Form III which displays a dehydration featurecalculated as a 3.7% weight loss which is consistent with thetheoretical weight loss of 3.7% for a hemihydrate. Analysis by DSCfurther confirms the TGA results, where only Form III shows adehydration event at about 95° C. The individual DSC traces furtherreveal a melting/decomposition endotherm at about 200-201° C. for eachof the three forms.

DVS data for each of the three crystal forms reveals the hygroscopicnature of both Forms I and II, which readily adsorb moisture at RHgreater than about 40-60% RH. In addition, both Forms I and II werecalculated to adsorb about 3.8 wt % moisture between about 40 and about80% RH which is consistent with conversion to the hemihydrate (FormIII). XRPD carried out on both Forms I and II after the DVS cycleconfirmed this conversion. In contrast, the DVS data in connection withForm III shows that it is substantially non-hygroscopic, adsorbing lessthan 0.5 wt % water at 90% RH and the XRPD pattern showed no change incrystalline form after the DVS cycle.

X-ray powder diffraction data for each of the three forms reveal similarpatterns. In fact, the diffraction patterns of Forms I and II shareessentially the same peaks, except that Form II has at least one uniquepeak at about 11.4° (2θ) which is not substantially present indiffraction patterns of Form I. Because both Forms I and II arehygroscopic, diffraction patterns obtained for these forms were oftencombined with peaks from the hemihydrate, Form III. The diffractionpattern of Form III differs significantly from the diffraction patternsof both Forms I and II, having several unique peaks. Exemplary peaksunique to Form III are set out in Table 1 above. X-ray powderdiffraction peaks for each of the three forms are compared in Table 2below.

TABLE 2 Form I Form II Form III degrees (2θ) degrees (2θ) degrees (2θ)6.5 6.5 10.2 9.6 9.6 12.7 10.2 10.2 13.7 12.9 11.4 14.9 17.1 12.9 15.417.5 17.1 15.8 17.8 17.5 16.7 18.5 17.8 18.5 19.5 18.5 18.9 19.8 19.519.2 20.1 19.8 20.1 20.5 20.1 20.5 21.3 20.5 21.4 21.6 21.3 22.8 22.321.6 23.2 23.7 22.3 23.5 24.6 23.7 24.0 25.3 24.6 24.2 25.9 25.3 24.727.6 25.9 25.3 27.9 27.6 25.7 28.3 27.9 26.0 28.7 28.3 26.5 29.5 28.726.9 29.8 29.5 27.6 30.3 29.8 28.2 30.9 30.3 29.0 31.3 30.9 30.0 32.631.3 30.3 32.9 32.6 30.8 32.9 31.1 32.0 32.3 32.7 33.3 33.8 35.8

Hemihydrate

In a first aspect of the invention, the present invention provides acompound which is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate.

In some embodiments, the hemihydrate has an X-ray powder diffractionpattern characteristic of Form III comprising peaks, in tennis of 2θ, atabout 13.7° and about 14.9°. In further embodiments, the hemihydrate hasan X-ray powder diffraction pattern comprising peaks, in terms of 2θ, atabout 13.7°, about 14.9°, about 15.4°, about 15.8°, and about 16.7°. Inyet further embodiments, the hemihydrate has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 13.7°, about 14.9°,about 15.4°, about 15.8°, about 16.7°, about 20.1°, or about 21.4°. Inyet further embodiments, the hemihydrate has an X-ray powder diffractionpattern substantially as shown in FIG. 11, wherein by “substantially” ismeant that the reported peaks can vary by about ±0.2°.

In some embodiments, the hemihydrate has a differential scanningcalorimetry trace comprising a relatively broad dehydration endotherm atabout 90 to about 110° C. (e.g., about 95° C.). In addition, thedifferential scanning calorimetry trace comprises a further endotherm atabout 200° C. In yet further embodiments, the hemihydrate has adifferential scanning calorimetry trace substantially as shown in FIG.10, wherein by “substantially” is meant that the reported DSC featurecan vary by about ±4°.

In some embodiments, the hemihydrate has a crystal habit which is rods,thin-plates, blocks, or a mixture thereof.

In some embodiments, the hemihydrate has a dynamic vapor sorptionprofile substantially as shown in FIG. 8, wherein by “substantially” ismeant that the reported DVS features can vary by about ±5% RH.

In some embodiments, the hemihydrate has a thermogravimetric analysisprofile showing about 3.7% weight loss corresponding to loss of water.In further embodiments, the hemihydrate has a thermogravimetric analysisprofile substantially as shown in FIG. 9, wherein by “substantially” ismeant that the reported TGA features can vary be about ±5° C.

The hemihydrate can be prepared by any of the suitable procedures knownin the art for preparing hydrates of compounds. In some embodiments, thehemihydrate can be prepared by at least partially dissolving(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridein a crystallizing solvent containing water, and inducing precipitationof the hemihydrate from the crystallizing solvent.

The crystallizing solvent can be any solvent or mixture of solvents thatat least partially dissolves(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideand contains water. In some embodiments, the crystallizing solventcontains an alcohol, water, and a hydrocarbon. Suitable alcoholsinclude, for example, methanol, ethanol, 2-nitroethanol,2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol,2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol,t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycolmonomethyl ether, diethylene glycol monoethyl ether, cyclohexanol,benzyl alcohol, phenol, or glycerol. In some embodiments, the alcohol isispropanol (2-propanol). Suitable hydrocarbons include, for example,benzene, cyclohexane, pentane, hexane, toluene, cycloheptane,methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane,indane, nonane, or naphthalene. In some embodiments, the hydrocarbon iscyclohexane.

In some embodiments, the weight ratio of alcohol to water in thecrystallizing solvent is about 35:1 to about 25:1, about 32:1 to about27:1, or about 30:1 to about 28:1. In some embodiments, the weight ratioof alcohol to water is about 29:1. In some embodiments, the weight ratioof alcohol plus water to hydrocarbon in the crystallizing solvent isabout 5:1 to about 2:1, about 3:1 to about 2:1, or about 2.5:1. In someembodiments, the weight ratio of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideto crystallizing solvent (e.g., alcohol plus water plus hydrocarbon) isabout 1:2 to about 1:15, about 1:6 to about 1:10, or about 1:8.

In some embodiments, the mixture containing the crystallizing solventand (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride is maintained at and/or heated to a temperature of about40 to about 80, about 50 to about 70, or about 60° C. prior to inducingprecipitation.

In some embodiments, the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideis substantially dissolved in the crystallizing solvent prior toinducing precipitation. Substantial dissolution can be achieved byheating the mixture to a suitable temperature such as between about 40and about 80° C. (e.g., about 60° C.).

Precipitation of the hemihydrate product can be induced by cooling themixture containing the crystallizing solvent and(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.In some embodiments, the mixture is cooled to a temperature of about −15to about 15° C. In some embodiments, the mixture is cooled to atemperature of about −5 to about 10° C. In further embodiments, themixture is cooled to a temperature of about 0 to about 5° C.

In some embodiments, the present invention provides a compound which is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideor hydrate thereof, wherein the compound or hydrate thereof gains lessthan about 1.0%, less than about 0.5%, or less than about 0.2% weightafter undergoing a dynamic vapor sorption cycle. The weight gain (ifany) can be measured as the difference between the sample weight at thebeginning of the cycle and at the end of the cycle. These two pointstypically occur at or near the same relative humidity (RH) value. Forexample, a cycle might be started at about 0% RH to about 20% RH, run toabout 85% to about 100% RH, and then returned to the starting RH point.In some embodiments, weight gain is measured at a starting/ending pointof about 5% RH, 10% RH, or 15% RH. In some embodiments, the cycle isruns through a maximum RH of about 85%, about 90%, about 95%, or about100%. In some embodiments, the sample shows weight gain of more thanabout 1%, more than about 2%, or more than about 5% during the cycle atabout 80% or greater RH. In some embodiments, the present inventionprovides a compound which is(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideor hydrate thereof having a dynamic vapor sorption profile substantiallyas shown in FIG. 12.

Form I

In a second aspect, the present invention is directed to a crystallineform of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride (Form I) having an X-ray powder diffraction patterncomprising peaks, in terms of 2θ, at about 6.5°, about 9.6°, and about10.2°. In some embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 6.5°,about 9.6°, about 10.2°, about 12.9, about 17.1°, about 17.5°, and about17.8°. In further embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising peaks, in terms of 2θ, at about 6.5°,about 9.6°, about 10.2°, about 12.9, about 17.1°, about 17.5°, about17.8°, about 18.5°, about 19.5°, and about 19.8°. In yet furtherembodiments, the crystalline form has an X-ray powder diffractionpattern comprising substantially no peak (e.g., where intensity is lessthan about 5% of the most intense peak) at about 10.5° to about 11.5°.In yet further embodiments, the crystalline form has an X-ray powderdiffraction pattern comprising substantially no peak at about 11.4°. Inyet further embodiments, the crystalline form has an X-ray powderdiffraction pattern substantially as shown in FIG. 3, wherein by“substantially” is meant that the reported peaks can vary by about±0.2°.

In some embodiments, the crystalline form has a differential scanningcalorimetry trace comprising an endotherm at about 201° C. In furtherembodiments, the crystalline form has a differential scanningcalorimetry trace substantially as shown in FIG. 2, wherein by“substantially” is meant that the reported DSC features can vary byabout ±4°.

In some embodiments, the crystalline form has a crystal habit which isgranular.

In some embodiments, the crystalline form has a dynamic vapor sorptionprofile substantially as shown in FIG. 4, wherein by “substantially” ismeant that the reported DVS features can vary by about ±5% RH.

In some embodiments, the crystalline form has a thermogravimetricanalysis profile substantially as shown in FIG. 1, wherein by“substantially” is meant that the reported TGA features can vary beabout ±5° C.

Form I can be prepared by any of the suitable procedures known in theart for preparing crystalline polymorphs. In some embodiments, Form Ican be prepared by heating crystalline(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride,where the crystalline(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecontains one or more crystalline forms other than Form I. For example,Form I can be prepared by heating samples containing Forms II or III(hemihydrate), or mixtures thereof. In some embodiments, Forms II or IIIor mixtures thereof, can be heated to a temperature of at least about60° C. for time and under conditions suitable for forming Form I. Insome embodiments, Forms II or III or mixtures thereof can be heated toat temperature of at least about 60° C. for at least about 2 hours.

Form II

In a third aspect of the invention, the invention provides a crystallineform of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride (Form II) having an X-ray powder diffraction patterncomprising at least one peak, in terms of 2θ, at about 11.4°. In someembodiments, the crystalline form has an X-ray powder diffractionpattern comprising peaks, in terms of 2θ, at about 6.5°, about 9.6°,about 10.2°, and about 11.4°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern comprising peaks, in terms of2θ, at about 6.5°, about 9.6°, about 10.2°, about 11.4°, about 12.9°,about 17.1°, about 17.5°, and about 17.7°. In some embodiments, thecrystalline form has an X-ray powder diffraction pattern comprisingpeaks, in terms of 2θ, at about 6.5°, about 9.6°, about 10.2°, about11.4°, about 12.9, about 17.1°, about 17.5°, about 17.8°, about 18.5°,about 19.5°, and about 19.8°. In some embodiments, the crystalline formhas an X-ray powder diffraction pattern substantially as shown in FIG.7, wherein by “substantially” is meant that the reported peaks can varyby about +0.2°.

In some embodiments, Form II has a differential scanning calorimetrytrace comprising an endotherm at about 201° C. In further embodiments,Form I has a differential scanning calorimetry trace substantially asshown in FIG. 6, wherein by “substantially” is meant that the reportedDSC feature can vary by about ±4° C.

In some embodiments, Form II has a crystal habit which is rods.

In some embodiments, Form II has a dynamic vapor sorption profilesubstantially as shown in FIG. 8, wherein by “substantially” is meantthat the reported DVS features can vary by about ±5% RH.

In some embodiments, Form II has a thermogravimetric analysis profilesubstantially as shown in FIG. 5, wherein by “substantially” is meantthat the reported TGA features can vary be about ±5° C.

Form II can be prepared by any of the suitable procedures known in theart for preparing crystalline polymorphs. For example, Form II can beprepared by dissolving(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridein an anhydrous crystallizing solvent and inducing precipitation such asby cooling or addition of anti-solvent. In some embodiments, Form II canbe prepared by combining(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (free base) ina hydrocarbon solvent to form a mixture; optionally removing water fromthe mixture to form a dehydrated mixture; and adding HCl and alcohol tothe dehydrated mixture. Suitable alcohols and hydrocarbon solvents arelisted hereinabove. In some embodiments, the hydrocarbon solvent iscyclohexane. In further embodiments, the alcohol is isopropanol. In someembodiments, addition of the alcohol is carried out over the time periodof about 15 minutes to about 2 hours. In some embodiments, the weightratio of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine tocyclohexane is about 1:20 to about 1:10, about 1:17 to about 1:12, orabout 1:10 to about 1:5, or about 1:7 to about 1:8. In furtherembodiments, the weight ratio of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine to alcohol isabout 1:1 to about 1:10 about 1:2 to about 1:5, or about 1:3.

Removal of water from the solvent mixture can be carried out by any ofroutine methods in the art such as by incubation with molecular sievesor by azeotropic distillation. Final water content of the mixture afterremoving water can be less than about 0.1, preferably less than about0.05, or more preferably less than about 0.03 wt %. If the water contentof the solvent mixture is sufficiently low (e.g., less than about 0.1 wt%), the water removal step can be omitted.

During the formation of the salt, the HCl (e.g., HCl gas) can be addedin molar excess relative to(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.

Compositions

The present invention further provides compositions containing one ormore of the three crystal forms of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.In some embodiments, the compositions of the invention include at leastabout 50, about 60, about 70, about 80, about 90, about 95, about 96,about 97, about 98, or about 99% by weight of the hemihydrate (e.g.,Form III). In some embodiments, the compositions of the inventioninclude at least about 50, about 60, about 70, about 80, about 90, about95, about 96, about 97, about 98, or about 99% by weight of Form I. Insome embodiments, the compositions of the invention include at leastabout 50, about 60, about 70, about 80, about 90, about 95, about 96,about 97, about 98, or about 99% by weight of Form II. In someembodiments, the compositions of the invention contain a mixture of twoor more of Forms I, II, and HI. In some embodiments, compositions of theinvention include Form I, Form II or the hemihydrate and apharmaceutically acceptable carrier.

Methods

The crystal forms of the invention have activity as 5-HT_(2C) receptoragonists. Accordingly, the crystal forms of the invention can be used inmethods of agonizing (e.g., stimulating, increasing activity of, etc.)the 5-HT_(2C) receptor by contacting the receptor with any one or moreof the crystal forms, or compositions thereof, described herein. Infurther embodiments, the crystal forms of the invention can be used toagonize 5-HT_(2C) receptors in an individual in need of such agonizingby administering a therapeutically effective amount of a crystal form ofthe invention.

The present invention further provides methods of treating diseasesassociated with the 5-HT_(2C) receptor in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a crystal form of thepresent invention or a pharmaceutical composition thereof. Examplediseases can include any disease, disorder or condition that is directlyor indirectly linked to expression or activity of the 5-HT_(2C)receptor, including under-expression or abnormally low activity of the5-HT_(2C) receptor.

Example diseases include disorders of the central nervous system; damageto the central nervous system; cardiovascular disorders;gastrointestinal disorders; diabetes insipidus, and sleep apnea. Exampledisorders of the central nervous system include depression, atypicaldepression, bipolar disorders, anxiety disorders, obsessive-compulsivedisorders, social phobias or panic states, sleep disorders, sexualdysfunction, psychoses, schizophrenia, migraine and conditionsassociated with cephalic pain or other pain, raised intracranialpressure, epilepsy, personality disorders, age-related behavioraldisorders, behavioral disorders associated with dementia, organic mentaldisorders, mental disorders in childhood, aggressivity, age-relatedmemory disorders, chronic fatigue syndrome, drug and alcohol addiction,obesity, bulimia, anorexia nervosa and premenstrual tension.

The present invention further provides methods of decreasing food intakeof a mammal by administering a therapeutically effective amount of acrystal form of the invention.

The present invention further provides methods for inducing satiety in amammal by administering a therapeutically effective amount of a crystalform of the invention.

The present invention further provides methods for controlling weightgain of a mammal by administering a therapeutically effective amount ofa crystal form of the invention.

The present invention further provides methods of treating obesity byadministering to a patient a therapeutically effective amount of acrystal form of the invention.

In some embodiments, the above methods further comprise the step ofidentifying a patient, where the patient is in need of treatment for theparticular disease being treated, wherein the identifying step isperformed prior to administration to the patient of the therapeuticallyeffective amount of the crystal form of the invention.

As used herein, the term “treating” refers to, for example, preventing,inhibiting, as well as ameliorating a disease, condition or disorder inan individual.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology)such as stabilizing viral load in the case of a viral infection; and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology) such aslowering viral load in the case of a viral infection.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the crystal forms of the invention canbe administered in the form of pharmaceutical compositions. Thesecompositions can be administered by a variety of routes including oral,rectal, transdermal, topical, subcutaneous, intravenous, intramuscular,and intranasal, and can be prepared in a manner well known in thepharmaceutical art.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the crystal forms of theinvention above in combination with one or more pharmaceuticallyacceptable carriers. In making the compositions of the invention, theactive ingredient is typically mixed with an excipient, diluted by anexcipient or enclosed within such a carrier in the form of, for example,a capsule, sachet, paper, or other container. When the excipient servesas a diluent, it can be a solid, semi-solid, or liquid material, whichacts as a vehicle, carrier or medium for the active ingredient. Thus,the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, suppositories, sterile injectablesolutions, and sterile packaged powders.

In preparing a formulation, the crystal form can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the crystal form is substantially insoluble, it can bemilled to a particle size of less than 200 mesh. If the crystal form issubstantially water soluble, the particle size can be adjusted bymilling to provide a substantially uniform distribution in theformulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 100 mg, more usually about 10 to about30 mg, of the active ingredient. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient.

The crystal form can be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the crystal form actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual crystal form administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of a crystalform of the present invention. When referring to these preformulationcompositions as homogeneous, the active ingredient is typicallydispersed evenly throughout the composition so that the composition canbe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules. This solid preformulation is thensubdivided into unit dosage forms of the type described above containingfrom, for example, 0.1 to about 500 mg of the active ingredient of thepresent invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the crystal forms and compositions of thepresent invention can be incorporated for administration orally or byinjection include aqueous solutions, suitably flavored syrups, aqueousor oil suspensions, and flavored emulsions with edible oils such ascottonseed oil, sesame oil, coconut oil, or peanut oil, as well aselixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of crystal form or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, earners, or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of the crystal forms of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the crystal form, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a crystal form of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecrystal forms of the invention can be provided in an aqueousphysiological buffer solution containing about 0.1 to about 10% w/v ofthe compound for parenteral adminstration. Some typical dose ranges arefrom about 1 μg/kg to about 1 g/kg of body weight per day. In someembodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kgof body weight per day. The dosage is likely to depend on such variablesas the type and extent of progression of the disease or disorder, theoverall health status of the particular patient, the relative biologicalefficacy of the crystal form selected, formulation of the excipient, andits route of administration. Effective doses can be extrapolated fromdose-response curves derived from in vitro or animal model test systems.

The crystal forms of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as anti-viral agents, antibodies, immunesuppressants, anti-inflammatory agents and the like.

In order that the invention disclosed herein may be more efficientlyunderstood, examples are provided below. It should be understood thatthese examples are for illustrative purposes only and are not to beconstrued as limiting the invention in any manner.

EXAMPLES Example 1 Preparation of Hydrochloric Acid Salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a clean, dry 25 mL round bottom flask were added(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free amine(220 mg), 3 mL methylene chloride, and 1.74 mL of 1M HCl in ether. Themixture was stirred for 5 minutes at room temperature. The solvent wasremoved under reduced pressure to give a white solid, the HCl salt. Thesalt was re-dissolved in methylene chloride (3 mL) and an additional1.74 mL of 1 M HCl was added and the solution was again stirred at roomtemperature for 5 minutes. The solvent was removed under reducedpressure to give the desired HCl salt of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine (190 mg crudeweight, 95% yield). NMR data was consistent with the desired product.

¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m,2H), 2.8-3.0 (m, 3H), 1.5 (d, 3H, J=7 Hz).

Example 2 Preparation of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate (Form III)

At 20 to 25° C., 160 g, 689 mM of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideis treated under a nitrogen atmosphere with 359.36 g of isopropanol. Theresulting mixture is heated to 60° C. providing a clear solution. Afterthe desired temperature is reached, 12.43 g of water are added followedby 960 g of cyclohexane which are added at 60 to 40° C. Afterwards thesolution is cooled over 2 hours with slow stirring (at 160 rpm) to 20 to25° C. After crystallization of the product is observed the resultingsuspension is cooled to 0 to 5° C. and stirred afterwards for additional3 h at 0 to 5° C. The suspension is filtered and the filter cake iswashed with 160 g of cyclohexane via the reactor and further 160 g ofcyclohexane. From this process 176.81 g of a colorless wet product wasobtained, which was dried at 35 to 45° C., preferentially 40° C., at 50mbar, 153.03 g (95.3 weight %) of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate was obtained as a colorless crystalline solid.

Example 3 Preparation of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecrystalline Form II

Approximately 6.6 g of the free base(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolvedin cyclohexane to a volume of about 130 mL. The water content wasreduced by azeotropic distillation to a level of less than 0.03%.Further cyclohexane was charged to the flask as required to maintain thesame volume. The clear solution was filtered and a mixture of 3.06 g,83.9 mmol hydrochloric acid gas and 19.38 g isopropanol was added over60 min at an internal temperature 20° C. The resulting suspension wasstirred for at least 2 h, before being filtered. The filter cake waswashed with 60 g of acetone cooled to 0-10° C. and the product (9.19 g)was dried at 60° C. at 30 mbar to provide 5.88 g of Form II.

Example 4 Preparation of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecrystalline Form I

Form I was prepared by heating a sample of either Form II (e.g.,prepared according to Example 2) or Form III (e.g., prepared accordingto Example 1) to a temperature of about 160° C. in a TGA furnace forabout 15 min when heated at a rate of about 10° C./min. Conversion toForm I was detected by XRPD analysis.

Example 5 Stability of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecrystalline Form I

A sample of Form I was heated to 160° C. in a TGA furnace for about 15min when heated at a rate of about 10° C./min. XRPD analysis showed nochange in crystal form after heating.

Example 6 Heat stability of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecrystalline Form III

A sample of Form III was heated to 60° C. for at least 2 hours. XRPDanalysis showed substantially no change in crystal form after heating.

A sample of Form III was heated to 60° C. for one day. XRPD analysisshowed partial conversion to Form I after heating.

A sample of Form III was heated to 80° C. for 30 minutes. XRPD analysisshowed partial conversion to Form I after heating.

A sample of Form III was heated to 80° C. for 1 day. XRPD analysisshowed partial conversion to Form I after heating.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patents,patent applications, and journal literature, cited in the presentapplication is incorporated herein by reference in its entirety.

1.-40. (canceled)
 41. A crystal form of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(Form I).
 42. A composition comprising the crystal form of claim
 41. 43.A composition comprising the crystal form of claim 41 and apharmaceutically acceptable carrier.
 44. A method of treatment ofobesity comprising administering to an individual in need of suchtreatment a therapeutically effective amount of the crystal form ofclaim
 41. 45. A method of decreasing food intake comprisingadministering to an individual in need of such administration atherapeutically effective amount of the crystal form of claim
 41. 46. Amethod of inducing satiety comprising administering to an individual inneed of such administration a therapeutically effective amount of thecrystal form of claim
 41. 47. A method of controlling weight gaincomprising administering to an individual in need of such administrationa therapeutically effective amount of the crystal form of claim
 41. 48.A process for preparing a crystal form of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(Form I) comprising the step of: heating crystalline(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride,where the crystalline(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecontains one or more crystalline forms other than Form I.
 49. Theprocess of claim 48, wherein the crystalline(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridecomprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride (Form II).
 50. The process of claim 48, wherein thecrystalline (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride comprises(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloridehemihydrate (Form III).
 51. The process of claim 48, wherein thecrystalline (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride comprises a mixture of(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(Form II) and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride hemihydrate (Form III).
 52. The process of claim 48,wherein the crystalline(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochlorideis heated at a temperature of at least about 60° C.
 53. A crystal formof (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride (Form I) prepared by the process of claim
 48. 54. A methodof preparing a pharmaceutical composition comprising mixing(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(Form I) with a pharmaceutically acceptable carrier.
 55. The method ofclaim 14, wherein the(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride(Form I) is prepared by a method of claim
 48. 56. A method according toclaim 54, further comprising forming the pharmaceutical composition intoa tablet, a pill, a powder, a soft or hard gelatin capsule, or a sterilepackaged powder.
 57. A solid pharmaceutical composition prepared by themethod of claim
 54. 58. A solid pharmaceutical composition prepared bythe method of claim 56, wherein the pharmaceutical composition is in aform chosen from a tablet, a pill, a powder, a soft or hard gelatincapsule, or a sterile packaged powder.